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Eur J Med Chem. 2016 Jan 27;108:564-576. doi: 10.1016/j.ejmech.2015.12.028. Epub 2015 Dec 17.

O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1.

Author information

1
Department of Chemistry, Bryn Mawr College, 101 N. Merion Ave., Bryn Mawr, PA 19010-2899, USA. Electronic address: wmalacho@brynmawr.edu.
2
Department of Chemistry, Bryn Mawr College, 101 N. Merion Ave., Bryn Mawr, PA 19010-2899, USA.
3
Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
4
Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.
5
Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA; Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA 19104, USA; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19104, USA.
6
Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA; Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19104, USA. Electronic address: mullera@mlhs.org.

Abstract

Indoleamine 2,3-dioxygenase-1 (IDO1) is a promising therapeutic target for the treatment of cancer, chronic viral infections, and other diseases characterized by pathological immune suppression. Recently important advances have been made in understanding IDO1's catalytic mechanism. Although much remains to be discovered, there is strong evidence that the mechanism proceeds through a heme-iron bound alkylperoxy transition or intermediate state. Accordingly, we explored stable structural mimics of the alkylperoxy species and provide evidence that such structures do mimic the alkylperoxy transition or intermediate state. We discovered that O-benzylhydroxylamine, a commercially available compound, is a potent sub-micromolar inhibitor of IDO1. Structure-activity studies of over forty derivatives of O-benzylhydroxylamine led to further improvement in inhibitor potency, particularly with the addition of halogen atoms to the meta position of the aromatic ring. The most potent derivatives and the lead, O-benzylhydroxylamine, have high ligand efficiency values, which are considered an important criterion for successful drug development. Notably, two of the most potent compounds demonstrated nanomolar-level cell-based potency and limited toxicity. The combination of the simplicity of the structures of these compounds and their excellent cellular activity makes them quite attractive for biological exploration of IDO1 function and antitumor therapeutic applications.

KEYWORDS:

Antitumor therapy; IDO1 inhibition; O-alkylhydroxylamines; Rational drug design

PMID:
26717206
PMCID:
PMC4724314
DOI:
10.1016/j.ejmech.2015.12.028
[Indexed for MEDLINE]
Free PMC Article

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